Abstract

BACKGROUND:

METHODS:

We conducted a randomized trial of oral antiretroviral therapy for use as preexposure prophylaxis among HIV-1-serodiscordant heterosexual couples from Kenya and Uganda. The HIV-1-seronegative partner in each couple was randomly assigned to one of three study regimens--once-daily tenofovir (TDF), combination tenofovir-emtricitabine (TDF-FTC), or matching placebo--and followed monthly for up to 36 months. At enrollment, the HIV-1-seropositive partners were not eligible for antiretroviral therapy, according to national guidelines. All couples received standard HIV-1 treatment and prevention services.

RESULTS:

We enrolled 4758 couples, of whom 4747 were followed: 1584 randomly assigned to TDF, 1579 to TDF-FTC, and 1584 to placebo. For 62% of the couples followed, the HIV-1-seronegative partner was male. Among HIV-1-seropositive participants, the median CD4 count was 495 cells per cubic millimeter (interquartile range, 375 to 662). A total of 82 HIV-1 infections occurred in seronegative participants during the study, 17 in the TDF group (incidence, 0.65 per 100 person-years), 13 in the TDF-FTC group (incidence, 0.50 per 100 person-years), and 52 in the placebo group (incidence, 1.99 per 100 person-years), indicating a relative reduction of 67% in the incidence of HIV-1 with TDF (95% confidence interval [CI], 44 to 81; P<0.001) and of 75% with TDF-FTC (95% CI, 55 to 87; P<0.001). Protective effects of TDF-FTC and TDF alone against HIV-1 were not significantly different (P=0.23), and both study medications significantly reduced the HIV-1 incidence among both men and women. The rate of serious adverse events was similar across the study groups. Eight participants receiving active treatment were found to have been infected with HIV-1 at baseline, and among these eight, antiretroviral resistance developed in two during the study.

CONCLUSIONS:

Oral TDF and TDF-FTC both protect against HIV-1 infection in heterosexual men and women. (Funded by the Bill and Melinda Gates Foundation; Partners PrEP ClinicalTrials.gov number, NCT00557245.).

For couples found to be ineligible for the study, the most common reasons for ineligibility were HIV-1 seropositive partners meeting national criteria for antiretroviral therapy initiation or already taking antiretroviral therapy (59%), and pregnancy (2%), breastfeeding (0.4%), or chronic active hepatitis B infection (10%) among HIV-1 seronegative partners. Less than 3% of couples screened out for creatinine elevation, glycosuria or proteinuria in the HIV-1 seronegative partner, which were exclusion criteria to minimize potential renal toxicity from tenofovir exposure.A total of 11 couples were enrolled and randomly allocated to one of the study arms but were later found to not meet all eligibility criteria; they were exited from the study at the time their ineligibility was discovered and their data were not included in the analysis.Retention of HIV-1 seropositive partners was ≥96% throughout the study follow-up period and was similar across randomization arms (data not shown).ITT, intention-to-treat; mITT modified intention-to-treat

P values for the modified intention-to-treat and the intention-to-treat analyses apply to the hypothesis of any evidence of efficacy (i.e,. testing against a null hypothesis of 0%); P values for the other comparisons correspond to a test for significant interaction in the site-stratified Cox proportional hazards model.*Subgroups defined by baseline characteristics. In the forest plots, dashed line indicates HR of 1.0 (0% efficacy for HIV-1 protection).†Per 100 person-years‡Of 45 HIV-1 infections in women, 5 (2 TDF, 0 FTC/TDF, 3 placebo) occurred in subjects who were not receiving study medication for >3 months due to pregnancy or breastfeeding.